Diabetes is one of the leading causes of cardiovascular death and disability in the United States and despite the treatment with insulin, patients with diabetes still have severe coronary vascular disease and altered cardiac metabolism. The goal of our studies is to better understand the mechanism responsible for diabetic cardiac disease especially the consequences of reduced production of NO on cardiac metabolism. Our approach will combine physiologic studies quantifying NO production and changes in cardiac metabolism over an extended period of time (5 weeks) after alloxan induced diabetes in chronically instrumented conscious dogs with in vitro studies of tissues from those dogs to determine microvessel NO production, ecNOS gene expression and the control of cardiac metabolism by NO. We will examine the potential consequences of alterations in NOS gene expression in the reduced NO production which we have already documented. A major focus of our studies both in vivo and in vitro will be the potential role of NO in the control of cardiac oxygen consumption and myocardial substrate utilization. We hypothesize that the loss of NO production during the development of diabetes contributes to the metabolic consequences of this disease. Since we have previously shown that exercise can upregulate NO production and mild regular exercise is beneficial in patients with diabetes we will test the hypothesis that regular exercise training will at least partially restore NO dependent control of tissue metabolism by increasing ecNOS. Furthermore, we will test the hypothesis that administration of Simvastatin (since "statins" increase the message half life for ecNOS and since our preliminary data suggest that NO production in vivo and in vitro is increased by statins) to correct the decrease in ecNOS enzyme, restores the cardiac metabolic dysfunction associated with diabetes. Thus, our aims will provide for an integrated approach to study: 1) the mechanism of the reduction in NO production we have found in diabetes, 2) the potential that this results in a cardiac metabolic defect, and, 3) the treatment of the cardiovascular complications of diabetes with exercise or Simvastatin corrects the cardiac metabolic defect.